Crystal form of imidazolone type compounds, and preparation method, pharmaceutical composition and use thereof

Abstract

The present invention relates to the crystal form of imidazolone type compounds, and a preparation method, pharmaceutical composition and use thereof, and falls within the field of pharmaceutical compound crystals. The crystal form provided by the present invention has a good stability, comprising good stability under the three extreme conditions of high temperature, high humidity and strong illumination, and can also maintain a good stability during the tablet compressing process. The crystal form provided by the present invention has good absorption and metabolism properties in vivo, comprising the drug concentration of blood, the drug concentration-time curve AUC, the half-life period, etc. In addition, the dissolving rate of the crystal form of the present invention is improved, wherein same is beneficial for the applications thereof in preparations.

What is claimed is: 
     
       1. A crystal of a pharmaceutically acceptable salt of Compound 1 represented by the following formula or a hydrate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         (a) said crystal is Crystal Form I of Compound 1 hydrochloride monohydrate, which is characterized by an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, which diffraction pattern comprises characteristic peaks expressed in 2-theta angle (°) at: 
       
       9.028±0.2, 11.196±0.2, 17.393±0.2, 22.504±0.2; or 
       9.028±0.2, 11.196±0.2, 15.406±0.2, 16.380±0.2, 17.393±0.2, 18.066±0.2, 18.739±0.2, 20.894±0.2, 22.504±0.2, 22.955±0.2; or 
       9.028±0.2, 11.196±0.2, 15.406±0.2, 16.380±0.2, 17.393±0.2, 18.066±0.2, 18.739±0.2, 20.894±0.2, 22.504±0.2, 22.955±0.2, 26.312±0.2, 26.918±0.2, 27.556±0.2, 35.168±0.2; or 
       9.028±0.2, 11.196±0.2, 12.200±0.2, 15.406±0.2, 16.380±0.2, 16.828±0.2, 17.393±0.2, 18.066±0.2, 18.739±0.2, 20.036±0.2, 20.894±0.2, 22.504±0.2, 22.955±0.2, 24.973±0.2, 
       25.505±0.2, 26.312±0.2, 26.918±0.2, 27.556±0.2, 28.403±0.2, 29.176±0.2, 31.586±0.2, 35.168±0.2;
 or 
 (b) said crystal is Crystal Form II of Compound 1 hydrochloride monohydrate, which is characterized by an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, which diffraction pattern comprises characteristic peaks expressed in 2-theta angle (°) at: 
 
       8.934±0.2, 11.126±0.2, 15.367±0.2, 22.437±0.2; or 
       8.934±0.2, 11.126±0.2, 12.161±0.2, 15.367±0.2, 16.289±0.2, 17.369±0.2, 18.037±0.2, 18.667±0.2, 20.896±0.2, 22.437±0.2, 22.928±0.2, 24.995±0.2, 26.269±0.2, 26.890±0.2, 27.574±0.2; or 
       8.486±0.2, 8.934±0.2, 11.126±0.2, 12.161±0.2, 13.317±0.2 15.367±0.2, 16.289±0.2, 16.742±0.2, 17.369±0.2, 18.037±0.2, 18.667±0.2, 19.966±0.2, 20.896±0.2, 22.437±0.2, 22.928±0.2, 24.995±0.2, 25.467±0.2, 26.269±0.2, 26.890±0.2, 27.213±0.2, 27.574±0.2, 28.366±0.2, 29.075±0.2, 35.001±0.2;
 or 
 (c) said crystal is Crystal Form III of Compound 1 hydrochloride, which is characterized by an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, which diffraction pattern comprises characteristic peaks expressed in 2-theta angle (°) at: 
 
       6.396±0.2, 7.115±0.2, 8.972±0.2, 10.803±0.2, 11.870±0.2, 18.542±0.2, 23.071±0.2; or 
       6.396±0.2, 7.115±0.2, 8.972±0.2, 10.803±0.2, 11.147±0.2, 11.870±0.2, 12.139±0.2, 15.417±0.2, 16.297±0.2, 16.559±0.2, 17.374±0.2, 18.074±0.2, 18.542±0.2, 19.310±0.2, 22.464±0.2, 23.071±0.2, 24.550±0.2, 25.843±0.2, 26.903±0.2, 28.737±0.2, 29.664±0.2, 35.016±0.2;
 or 
 (d) said crystal is Crystal Form IV of Compound 1 hydrochloride, which is characterized by an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, which diffraction pattern comprises characteristic peaks expressed in 2-theta angle (°) at: 
 
       6.178±0.2, 8.996±0.2, 11.170±0.2, 15.393±0.2, 16.343±0.2, 17.349±0.2, 18.064±0.2, 18.708±0.2, 19.479±0.2, 19.994±0.2, 20.901±0.2, 22.470±0.2, 22.935±0.2, 24.964±0.2, 25.504±0.2, 26.287±0.2, 26.920±0.2, 27.545±0.2; or 
       6.178±0.2, 6.614±0.2, 7.181±0.2, 7.470±0.2, 8.996±0.2, 11.170±0.2, 11.723±0.2, 12.183±0.2, 13.323±0.2, 14.412±0.2, 15.393±0.2, 16.343±0.2, 16.777±0.2, 17.349±0.2, 18.064±0.2, 18.708±0.2, 19.479±0.2, 19.994±0.2, 20.901±0.2, 22.470±0.2, 22.935±0.2, 24.964±0.2, 25.504±0.2, 26.287±0.2, 26.920±0.2, 27.545±0.2, 28.363±0.2, 28.841±0.2, 29.152±0.2, 31.487±0.2, 33.970±0.2, 35.136±0.2;
 or 
 (e) said crystal is Crystal Form V of Compound 1 hydrochloride dihydrate, which is characterized by an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, which diffraction pattern comprises characteristic peaks expressed in 2-theta angle (°) at: 
 
       6.181±0.2, 8.318±0.2, 18.223±0.2, 31.778±0.2; or 
       6.181±0.2, 7.226±0.2, 8.318±0.2, 9.524±0.2, 10.496±0.2, 12.037±0.2, 18.223±0.2, 27.421±0.2, 31.778±0.2;
 or 
 (f) said crystal is Crystal Form VI of Compound 1 hydrochloride dihydrate, which is characterized by an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, which diffraction pattern comprises characteristic peaks expressed in 2-theta angle (°) at: 
 
       7.489±0.2, 8.897±0.2, 11.140±0.2, 11.638±0.2, 13.348±0.2, 13.755±0.2, 16.110±0.2, 17.152±0.2, 18.782±0.2, 19.865±0.2, 20.891±0.2, 21.477±0.2, 25.245±0.2, 26.184±0.2, 26.431±0.2, 27.242±0.2, 28.489±0.2; or 
       7.489±0.2, 8.153±0.2, 8.897±0.2, 11.140±0.2, 11.638±0.2, 13.348±0.2, 13.755±0.2, 14.985±0.2, 15.467±0.2, 16.110±0.2, 17.152±0.2, 18.240±0.2, 18.782±0.2, 19.865±0.2, 20.891±0.2, 21.477±0.2, 22.333±0.2, 22.888±0.2, 25.245±0.2, 26.184±0.2, 26.431±0.2, 27.242±0.2, 28.489±0.2, 29.710±0.2;
 or 
 (g) said crystal is Crystal Form VII of Compound 1 hydrochloride dihydrate, which is characterized by an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, which diffraction pattern comprises characteristic peaks expressed in 2-theta angle (°) at: 
 
       6.264±0.2, 6.760±0.2, 7.556±0.2, 14.455±0.2, 20.123±0.2, 26.373±0.2; or 
       6.264±0.2, 6.760±0.2, 7.556±0.2, 11.414±0.2, 11.743±0.2, 12.488±0.2, 13.419±0.2, 14.455±0.2, 17.246±0.2, 18.099±0.2, 20.123±0.2, 21.082±0.2, 25.370±0.2, 26.373±0.2, 27.294±0.2. 
     
     
       2. A pharmaceutical composition comprising the crystal according to  claim 1  and at least one pharmaceutically acceptable carrier or auxiliary. 
     
     
       3. The crystal of  claim 1 , wherein said crystal is Crystal Form I of Compound 1 hydrochloride monohydrate. 
     
     
       4. A method for preparing the crystal according to  claim 3 , which is one of the following preparation methods A and B:
 preparation method A, comprising: 
 1) dissolving Compound 1 hydrochloride in water; 
 2) adding sodium chloride to the solution of step 1); and 
 3) cooling down, crystallizing, filtering, and drying to give Crystal Form I, 
 wherein in step 1), water is heated before or after the addition of Compound 1 hydrochloride to dissolve Compound 1 hydrochloride; wherein water is used in an amount 2-80 times the weight of Compound 1 hydrochloride; and the water is heated to 70-100° C.; 
 wherein in step 2), sodium chloride is added while maintaining the temperature of the solution of step 1); the amount of sodium chloride is controlled so that it makes up 0.1-26% of the total weight of the solution; 
 wherein the weight percentage content of sodium chloride is in the range from 10% to the saturated concentration; 
 wherein in step 3), the mixture is slowly cooled down to below 60° C. under stirring to crystallize, followed by filtration by suction, rinsing, and drying in vacuo at 15-35° C. to give Crystal Form I of Compound 1 hydrochloride monohydrate; 
 or, 
 preparation method B, comprising: 
 1) dissolving Compound 1 hydrochloride in an aqueous solution of ethanol; and 
 2) cooling down, crystallizing, filtering, and drying to give Crystal Form I; 
 wherein in step 1), the aqueous solution of ethanol is heated before or after the addition of Compound 1 hydrochloride to dissolve Compound 1 hydrochloride; wherein the amount of the aqueous solution of ethanol is 5-80 times the weight of Compound 1 hydrochloride; and the aqueous solution of ethanol is heated to 50-100° C.; 
 wherein the mass percentage of ethanol in the aqueous solution of ethanol is 30 to 99%; 
 wherein in step 2), the mixture is slowly cooled down to below 40° C. under stirring to crystallize, followed by filtration by suction, and drying in vacuo at 15 to 35° C. to give Crystal Form I of Compound 1 hydrochloride monohydrate. 
 
     
     
       5. The crystal of  claim 1 , wherein said crystal is Crystal Form II of Compound 1 hydrochloride monohydrate. 
     
     
       6. The crystal of  claim 1 , wherein said crystal is Crystal Form III of Compound 1 hydrochloride. 
     
     
       7. The crystal of  claim 1 , wherein said crystal is Crystal Form IV of Compound 1 hydrochloride. 
     
     
       8. The crystal of  claim 1 , wherein said crystal is Crystal Form V of Compound 1 hydrochloride dihydrate. 
     
     
       9. The crystal of  claim 1 , wherein said crystal is Crystal Form VI of Compound 1 hydrochloride dihydrate. 
     
     
       10. The crystal of  claim 1 , wherein said crystal is Crystal Form VII of Compound 1 hydrochloride dihydrate. 
     
     
       11. A method for preparing the crystal according to  claim 10 , which is one of the following preparation methods A and B:
 preparation method A, comprising: 
 1) dissolving Compound 1 hydrochloride in water; 
 2a) cooling the aqueous solution of step 1) to crystallize; or 2b) adding sodium chloride to the aqueous solution of step 1) and stirring to crystallize; and 
 3) filtering, and drying, to give Crystal Form VII; 
 wherein in step 1), the amount of water used is 10 to 500 times the weight of Compound 1 hydrochloride; water is heated before or after Compound 1 hydrochloride is added; a step of hot filtration to remove insolubles is optionally included; and the water is heated to 70-100° C.; 
 wherein in step 2a), the aqueous solution of step 1) is cooled down to below 40° C. to crystallize; 
 wherein in step 2b), the solution is stirred at below 40° C. crystallize; and the amount of sodium chloride is 1 to 15 times that of Compound 1 hydrochloride; 
 wherein in step 3), the filtering is by suction, and the drying is in vacuo; 
 or, 
 preparation method B, comprising: 
 mixing and beating one or more of the Crystal Forms I-VI with water for 3 days to give Crystal Form VII; 
 wherein the mixing and beating are performed at below 40° C.; and the amount of water used in the mixing and beating is 20 to 200 times the total weight of Crystal Forms I-VI. 
 
     
     
       12. A pharmaceutical composition comprising the crystal according to  claim 3  and at least one pharmaceutically acceptable carrier or auxiliary. 
     
     
       13. A pharmaceutical composition comprising the crystal according to  claim 5  and at least one pharmaceutically acceptable carrier or auxiliary. 
     
     
       14. A pharmaceutical composition comprising the crystal according to  claim 6  and at least one pharmaceutically acceptable carrier or auxiliary. 
     
     
       15. A pharmaceutical composition comprising the crystal according to  claim 7  and at least one pharmaceutically acceptable carrier or auxiliary. 
     
     
       16. A pharmaceutical composition comprising the crystal according to  claim 8  and at least one pharmaceutically acceptable carrier or auxiliary. 
     
     
       17. A pharmaceutical composition comprising the crystal according to  claim 9  and at least one pharmaceutically acceptable carrier or auxiliary. 
     
     
       18. A pharmaceutical composition comprising the crystal according to  claim 10  and at least one pharmaceutically acceptable carrier or auxiliary.